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United States Patent 3,123,623 6-AMlN0-4-PREGNENE-3,20-DIONE AND N-ACYL DERIVATIVES THEREOF Kanzo Sasaki, Osaka, Japan, assignor to Shionogi & Co., Ltd, Osaka, Japan No Drawing. Filed July 11, 1963, Ser. No. 294,446 Claims priority, application Japan July 17, 1%2 '7 Claims. (Cl. 269-3973) The present invention relates to 6-amino-4-pregnene- 3,20-dione and N-acyl derivatives thereof which are represented by the formula:

NIL-R (I) wherein R is a hydrogen atom or a lower alkanoyl group (e.g. acetyl, propionyl, butyryl, valeryl) and the ripple mark (5) represents a generic indication of aand [SI-configurations.

It is an object of the present invention to provide 6-amino-4-pregnene-3,20-dione and N-acyl derivatives thereof. Another object of the invention is to provide physiologically active 6-amino-4-pregnene-3,20-dione and N-acyl derivatives thereof. Other objects will be apparent to those conversant with the art to which this invention pertains.

The objective 6-amino-4-pregnene-3,ZO-dione and N-acyl derivatives thereof can be prepared from Sa-hydroxy- 6/3-aminopregnane-3,ZO-dione and N-acylates thereof according to the following scheme:

3,123,623 Patented Mar. 3, 1964 wherein R is a lower alkanoyl group (e.g. acetyl, propionyl, butyryl, valeryl).

The starting amine (Ila) and acylamine (IIb) are novel and can be prepared from a known compound, 500,600- epoxypregnane-3,20-dione 3,20-bisethyleneketal [Bowers et al.: Tetrahedron, vol. 7, p. 138 (1959)], by subjecting the latter to react with sodium azide in an inert solvent mediurn such as methanol, ethanol, ether, tetrahydrofuran and dioxane at a temperature from to 150 C. in a sealed tube and reducing the resulting Soc-hYCllOXY- 6/3-azidopregnane-3,20-3,20-bisethyleneketal with lithium aluminum hydride in an inert organic solvent medium such as benzene, ether, tetrahydrofuran and dioxane at a temperature from room temperature (15 to 30 C.) to the boiling point of the employed solvent, followed by deketalation in a conventional manner and, if necessary, acylation in a conventional manner.

According to the process of the present invention, the starting amine (Ila) or acylamine (11b) is treated with a dehydrating agent to give the corresponding A -amine (Ia) or M-acylamine (11)). As the dehydrating agent, there may be employed an acid such as hydrochloric acid, sulfuric acid, acetic acid and p-toluenesulfonic acid, a halogenating agent such as phosphorus oxychloride, phosphorus oxybromide and phosphorus trichloride or a sulfonylating agent such as thionyl chloride and thionyl bromide. As the configuration of the amino or acylamino group at the 6-position of the objective A -amine (la) or A -acylarnine (lb) is associated with the acidity of the reaction medium, a suitable selection of the dehydrating agent and the reaction solvent in accordance with the object is required. There is generally produced the A -6a-arnine (Ia) or A -6a-acyl amine (11)) under an ordinary acidic condition, because of the much greater stability of the same than the 65-isomer thereof. When the production of the A -6,B-

amine (Ia) or A -6fi-acylamine (lb') is intended, there is required a somewhat suppressed acidic condition. For

instance, a combination of a sulfonylating agent such as thionyl bromide with a base such as pyridine and picoline is advantageously used as the dehydrating agent for attaining this object. The reaction readily proceeds by treating the starting amine (Ila) or acylamine (111)) with the suitably selected dehydrating agent at a wide range of temperature, for instance, from -20 to C. (preferably while cooling with ice), if necessary in the presence of an inert solvent medium such as ether, dioxane, acetone, benzene and acetic acid. When the A -6fi-amine (162) or A -6fl-acylamine (111) is obtained, it may be further treated with an acidic substance such as hydrochloric acid whereby the same is readily converted into the corresponding oat-isomer. In general, the A -amine (Ia) is relatively unstable and can be difiicultly purified. Accordingly, it is acylated in a conventional procedure, e.g. treatment with a mixture of alkanoic anhydride and pyridine, to the corresponding M-acylamine (lb) which is stable and can be readily purified by a conventional procedure such as extraction and crystallization.

With respect to the hereinabove disclosure, it should be understood that it only illustrates a typical procedure for carrying out the present invention and some modifications may be apparent to those conversant with the art to which the present invention pertains without departing from the spirit of the invention. Such modifications include, for instance, the execution of the above disclosed reaction using 5a-hydroxy-6B-amino or acylamino-pregmane-3,20-dione 3,20-bisethyleneketal instead of the amine (Ila) or acylamine (115) as the starting material to produce the A -amine (Ia) or A -acylamine by one step.

The thus produced A -arnine (Ia) and A -acylamine (lb) are useful as CNS (central nervous system) depressing agents. For instance, 6a-acetylamino-4-pregnene-3, 20-dione produced anesthetic state for 6 to 8 hours in mice Weighing about 16 grams, when administered at a dose of 0.3 milligram per mouse by intra-peritoneal route.

The following examples are given solely for the purpose of illustration and are not intended to be construed as limitations of this invention.

Example 1 Rd NE:

A solution of a-hydroxy-fi-aminopregnane-BJO-dione p-toluenesulfonate (240 mg.) in glacial acetic acid (8 ml.) is bubbled with dried hydrogen chloride for 4-0 minutes. The reaction mixture is added to an aqueous solution of sodium hydroxide. The resulting mixture is saturated with sodium chloride and shaken with dichloromethane. The dichloromethane phase is shaken with 5% hydrochloric acid. The hydrochloric acid phase is made alkaline with sodium hydroxide, saturated with sodium chloride and extracted with dichlorornethane. The dichloromethane extract is washed with water, dried over anhydrous sodium sulfate and evaporated to give 60camino-4-pregnene-3,ZO-dione (54 mg.) as yellow crystals melting at 140 to 148 C. (decomp.).

IR: 1 H? 3388, 3308, 1794, 1660, 1610 cm? UV: k531i? 24-0 110 (6, 12,400)

5a-hydroxy-6fl-aminopregnane-3,ZO-dione is subjected to reaction in the same manner as above whereby 60L- amino-4-pregnene-3,20-dione is produced.

The starting material of this example, 506-hyd1'OXy6fiaminopregnane-3,20-dione, is produced from a known steroid, 5ct,6a epoxypregnane-3,20-dione 3,20-bi-sethyleneketal according to the following scheme:

Heating with sodium azide in ethanol at 150 C Ho N3 Refluxing with lithium aluminum hydride in tetrahydrofuran C Ha I C Treating with ptoluenosulionlc acid at 60 C.

Treating with sodium hydroxide O:

I E0 NH? 0502- -CI-Ia (F11) C=O no D III:

Example 2 NHCOOH: NHCOOH;

A solution of 5u-hydroxy-6fl-acetylaminopregnane- 3,20-dione (43 mg.) in glacial acetic acid (2 ml.) is bubbled with dried hydrogen chloride for 30 minutes while cooling with ice and then allowed to stand for 2 hours While cooling with ice. To the reaction mixture, there is added water (2 ml), and the resultant mixture is shaken with dichloromethane. The dichloromethane phase is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is crystallized from other and recrystallized from a mixture of acetone and ether to give 6u-acetylamino-4- pregnene-3,20-dione (23 mg.) as crystals melting at 122 to 124 C. +118i2 (0., 0.996 in chloroform).

UV: A322? 240 mu (6, 13,700). IR: filif 3436, 3326, 1703, 1675, 1664, 1621, 1513, 1506, 1361 cm.-

Analysis.-Calcd. for C H O N: C, 74.36; H, 8.75; N, 3.77 Found: C, 74.39; H, 9.00; N, 3.58.

The starting material of this example, 5a-hydroxy-6fiacetylaminopregnane-B,20-dione, is produced from 5ahydroxy 6B-arninopregnane-3,20-dione 3,20-bisethyleneketal according to the following scheme:

l 5 I IHg Treating with acetic auhydride and pyridine at 20 CHa C 0 Treating with p-toluenesulionie acid in acetone at 20 C. O

I 0 H 0 i NH0 0 CH3 NBC 0 CH3 Example 3 (EH: CH; )(330 C O i 0: 0: no

NHCOOH: NHCOGHa To a solution of a-hydroxy-6fl-acetylaminopregnane- 3,20-clione (316 mg.) in pyridine (5 ml.), there is added a solution of thionyl chloride (2 ml.) in pyridine (2 ml.) with stirring while cooling with ice. After continuation of stirring for 5 minutes while cooling with ice, the reaction mixture is added to water (150 ml.). The resulting mixture is saturated with sodium chloride and shaken with chloroform. The chloroform phase is washed with 5% hydrochloric acid, 5% sodium carbonate and Water in order, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting oil is treated with activated carbon and crystallized from a mixture of acetone and ether to give 6,8-acetylamino-4-pregnene-3,20-dione (140 mg.) as crystals melting at 228 to 230 C. [(11 +108i2 (c., 0.841 in chloroform) UV: x3333 2 m (6, 13,200 IR: 5:52 3450,3380, 1705, 1680, 1675, 1e20, 1500, 1363 (MIL-1 Analysis.-Calcd. for C H O N: C, 74.36; H, 8.95; N, 3.77. Found: C, 74.41; H, 9.05; N, 3.72.

0 Example 4 CH3 L o] on. \0 0:0

O i O I no NHGOCH: Nrroocrn A solution of 50a hydroxy-6p-acetylaminopregnane- 3,20-di0ne 3,20-bisethyleneketa1 (1.05 g.) in glacial acetic acid (20 ml.) is bubbled with dried hydrogen chloride for 45 minutes while cooling with ice. The reaction mixture is combined with water, saturated with sodium chloride and shaken with chloroform. The chloroform 'phase is washed with 5% sodium carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The oily residue is crystallized from a mixture of acetone and ether to give 6a-acetylamino-4-pregnane-3,20-dione (513 mg.) as crystals melting at 122 to 124 C.

To a solution of 5a-hydroxy-65-acetylaminopregnane- 3,20-dione 3,20-bisethyleneketal mg.) in a mixture of acetone (2 ml.) and dioxane (1 ml.), there is added p-toluenesulfonic acid mg), and the resulting mixture is stirred at room temperature (15 to 30 C.) for 17 hours. Then, the mixture containing Soc-hYdIOXY-Gfiacetylaminopregnane-3,ZO-dione is heated at 70 C. for 10 minutes to make a clear solution. After stirring at the same temperature for 3 hours, water is added thereto. The resultant mixture is shaken with chloroform. The chloroform phase is washed with 5% sodium carbomate and water in turn and evaporated. The residue is crystallized from a mixture of acetone and ether to give 6oc-acetylamino-4-pregnene-3,20-dione (35 mg.) as crystals melting at 122 to 124 C.

Example 6 C111: (EH; C=O o=0 i l o: 0:

1 IHo0oHi iIHoooLn A solution of 6B-acetylamino-4-pregnene-3,20-dione (50 mg.) in glacial acetic acid (1.5 ml.) is bubbled with dried hydrochloric acid for 40 minutes while cooling with 8 ice. The reaction mixture is combined with Water, satu- Having thus disclosed the invention what is claimed is: rated with sodium chloride and shaken with chloroform. 1. A compound of the formula: The chloroform phase is washed with sodium carbonate and Water and evaporated. The oily residue is fi crystallized from a mixture of acetone and ether to give 5 i=0 6a-acetyl-aminOA-pregnene-3,20-dione (40 mg.) as crys- I tals melting at 120 to 124 C.

Example 7 (3113 I E 10 1 0:0 0:0 0:

NHR I wherein R is a member selected from the group consisting of hydrogen and lower alkanoyl. 0= 0: 2. 6u-amino-4-pregnene-3,ZO-dione.

3. 6a-2II1lI10-4-PI6gI16I16-3,ZOWliOIlB N-lower alkanoate. NH, 5 1100011 0 4. 65-amino-4-pregnene-3,20 dione. 5. 6B-amino-4-pregnene-3,ZO-dione N-lower alkanoate. 6a-ammo-4-pregnene 3,ZO-drone 1s acetylated wlth ace- 6' 1 i 4 3 di tlC anhydnde in pyridine at room temperature (15 to 7 63- ty1amin0-4-pregnene-3,ZO-diOne. 30 C.) to produce 6a-acetylamino-4-pregnene-3,ZQ-dione. No references cited. 

1. A COMPOUND OF THE FORMULA: 